Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells Journal Article

Authors: Kang, D. W.; Choi, C. Y.; Cho, Y. H.; Tian, H.; Di Paolo, G.; Choi, K. Y.; Min, D. S.
Article Title: Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells
Abstract: Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models. Intestinal epithelial cell-specific PLD1 overexpression in Apc(Min/+) mice accelerated tumorigenesis with increased proliferation and nuclear β-catenin levels compared with Apc(Min/+) mice. Moreover, PLD1 inactivation suppressed the self-renewal capacity of colon cancer-initiating cells (CC-ICs) by decreasing expression of β-catenin via E2F1-induced microRNA (miR)-4496 up-regulation. Ultimately, low expression of PLD1 coupled with a low level of CC-IC markers was predictive of a good prognosis in CRC patients, suggesting in vivo relevance. Collectively, our data reveal that PLD1 has a crucial role in intestinal tumorigenesis via its modulation of the E2F1-miR-4496-β-catenin signaling pathway. Modulation of PLD1 expression and activity represents a promising therapeutic strategy for the treatment of intestinal tumorigenesis. © 2015 Kang et al.
Keywords: immunohistochemistry; signal transduction; genetics; pathophysiology; flow cytometry; mouse; animal; metabolism; animals; mice; apoptosis; microrna; physiology; carcinogenesis; blotting, western; western blotting; immunoprecipitation; tissue array analysis; mutagenesis, site-directed; real time polymerase chain reaction; tissue microarray; dna primers; primer dna; micrornas; intestine tumor; intestinal neoplasms; site directed mutagenesis; beta catenin; phospholipase d1; hek293 cells; in situ nick-end labeling; real-time polymerase chain reaction; dextran sulfate; phospholipase d; humans; human; hek293 cell line; azoxymethane; tunel assay
Journal Title: Journal of Experimental Medicine
Volume: 212
Issue: 8
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2015-07-27
Start Page: 1219
End Page: 1237
Language: English
DOI: 10.1084/jem.20141254
PUBMED: 26122663
PROVIDER: scopus
PMCID: PMC4516794
Notes: Article -- Export Date: 2 June 2016 -- Source: Scopus
Citation Impact
MSK Authors
  1. Huasong Tian
    8 Tian